Endoplasmic Reticulum is an extensive membrane system that forms part of the endomembrane system of eukaryotic cells. It consists of interconnected tubules, sheets and cisternal structures enclosed by a membrane that is continuous with the outer nuclear membrane. Two major forms are recognised, rough endoplasmic reticulum and smooth endoplasmic reticulum. Rough endoplasmic reticulum has ribosomes attached to its cytosolic surface and is particularly important in synthesis and initial processing of proteins destined for secretion, membranes and certain organelles. Smooth endoplasmic reticulum lacks attached ribosomes and participates in lipid synthesis, calcium storage, detoxification and other metabolic processes. The endoplasmic reticulum is not simply a static membrane network. Its shape, distribution and interactions with other organelles change continuously according to cellular needs.
Protein synthesis associated with rough endoplasmic reticulum begins when a ribosome translating a protein encounters an appropriate targeting signal. The signal is recognised by the signal recognition particle, which directs the ribosome and nascent polypeptide to a receptor on the endoplasmic reticulum membrane. Translation then continues with the growing protein entering the endoplasmic reticulum lumen or becoming inserted into the membrane. This process is called cotranslational translocation. Proteins entering the endoplasmic reticulum can undergo folding, disulfide bond formation, glycosylation and other forms of processing. Molecular chaperones and quality control systems monitor folding and prevent many incorrectly assembled proteins from progressing through the secretory pathway.
The endoplasmic reticulum is a major site of protein quality control. Newly synthesised proteins must attain appropriate three dimensional structures before they can perform their functions. Chaperones such as binding immunoglobulin protein assist protein folding within the endoplasmic reticulum lumen. Misfolded proteins can be retained and targeted for degradation through endoplasmic reticulum associated degradation, in which proteins are moved back to the cytosol and degraded by proteasomes.
If misfolded proteins accumulate beyond the capacity of the quality control system, cells activate the unfolded protein response. This response can reduce general protein synthesis, increase production of folding and quality control machinery and, if stress is prolonged or severe, contribute to programmed cell death.
Smooth endoplasmic reticulum has major roles in lipid and steroid metabolism. Enzymes embedded in its membranes synthesise phospholipids and other lipids required for cellular membranes. In steroid producing cells, specialised smooth endoplasmic reticulum participates in steroid hormone biosynthesis. The smooth endoplasmic reticulum of liver cells contains enzymes involved in detoxification and modification of many drugs and foreign chemicals. In muscle cells, a specialised form called the sarcoplasmic reticulum stores and releases calcium ions that regulate contraction. These specialised functions illustrate how the same fundamental membrane network can be adapted to different physiological requirements. The relative proportions of rough and smooth regions therefore vary greatly among cell types.
The endoplasmic reticulum is an important calcium reservoir and signalling compartment. Calcium ions stored within the lumen can be released into the cytoplasm through regulated channels, producing signals that influence muscle contraction, secretion, metabolism and other processes. Calcium must then be returned to the endoplasmic reticulum by ATP dependent pumps to restore resting conditions. Disturbance of calcium homeostasis can influence protein folding because the endoplasmic reticulum lumen requires particular ionic and redox conditions for proper processing. Calcium signalling therefore intersects with protein quality control, metabolism and cell survival. Interactions between the endoplasmic reticulum and mitochondria also facilitate coordinated calcium transfer and metabolic regulation.
The endoplasmic reticulum participates in membrane production and intracellular transport. Lipids synthesised in the endoplasmic reticulum contribute to the membranes of the endoplasmic reticulum itself and are redistributed to other cellular compartments. Proteins and lipids destined for the Golgi apparatus are packaged into transport carriers that bud from specialised regions of the endoplasmic reticulum. Vesicle formation, movement and fusion require coordinated action by coat proteins, small GTPases, tethering factors and SNARE proteins. The endoplasmic reticulum therefore acts as an early organisational centre for the secretory pathway. Its continuity with the nuclear envelope also provides a physical and functional connection between genome organisation and membrane biogenesis.
Endoplasmic reticulum morphology depends on cytoskeletal interactions and cellular geometry. Microtubules and associated motor proteins help position and remodel the endoplasmic reticulum throughout the cytoplasm. Tubules can extend, retract and form junctions, while sheets are particularly prominent in regions supporting high levels of protein synthesis. The endoplasmic reticulum also forms membrane contact sites with mitochondria, lysosomes, peroxisomes and the plasma membrane. These contact regions allow selected lipids, calcium and signalling information to move or be exchanged without conventional vesicle transport. Such contacts demonstrate that organelles are not isolated compartments but interconnected components of an integrated cellular system.
Defects in endoplasmic reticulum function can contribute to disease through disturbed protein folding, lipid metabolism, calcium regulation and cellular stress responses. Secretory cells are particularly dependent on endoplasmic reticulum quality control because they produce large quantities of proteins. Pancreatic cells, antibody producing immune cells and other highly secretory cells can therefore be sensitive to disturbances in endoplasmic reticulum homeostasis. However, endoplasmic reticulum stress is not inherently pathological because controlled unfolded protein responses can be adaptive. A common misconception is that rough and smooth endoplasmic reticulum are completely separate organelles. They are instead structurally continuous regions of one interconnected membrane system with different local compositions and functions.
